Processes for the preparation of pesticidal compounds

ABSTRACT

The present application provides processes for making pesticidal compounds and compounds useful both as pesticides and in the making of pesticidal compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. application Ser. No. 14/517,591filed on Oct. 17, 2014, which claims the benefit of the following U.S.Provisional Patent Applications: Ser. No. 62/042,554 filed Aug. 27,2014; and Ser. No. 61/892,129 filed Oct. 17, 2013, the entiredisclosures of which are hereby expressly incorporated by reference intothis Application.

TECHNICAL FIELD

This application relates to efficient and economical synthetic chemicalprocesses for the preparation of pesticidal thioethers and pesticidalsulfoxides. Further, the present application relates to certain novelcompounds necessary for their synthesis. It would be advantageous toproduce pesticidal thioether and pesticidal sulfoxides efficiently andin high yield from commercially available starting materials.

DETAILED DESCRIPTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains.

As used herein, the term “alkynyl” denotes branched or unbranchedhydrocarbon chains having at least one C≡C.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone is a saturated cyclic hydrocarbon group, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl.

The term “thio” as used herein as part of another group refers to asulfur atom serving as a linker between two groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine.

The pesticidal thioethers of formula 3c

and the pesticidal sulfoxides of formula 3d

wherein,

-   -   R¹ is selected from the group consisting of C₁-C₄-haloalkyl and        C₁-C₄-alkyl-C₃-C₆-halocycloalkyl, and    -   R² is selected from the group consisting of C₁-C₄-alkyl and        C₂-C₄-alkynyl can be prepared by the methods illustrated in        Schemes 1 to 9.

In step a of Scheme 1, 3-hydrazinopyridine dihydrochloride is reactedwith methyl acrylate in the presence of a base such as sodium methoxideor sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one followedby chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphorylchloride (POCl₃) in a two-step process to yield dihydropyrazole chloride(5a). The first step may be conducted in a polar protic solvent such as,methanol (MeOH) or ethanol (EtOH), at a temperature from about 40° C. toabout 80° C. The second step may be conducted neat in phosphorylchloride at a temperature from about 40° C. to about 80° C. When thecrude product from the first step was neutralized, the second step canalso be conducted in a solvent like acetonitrile (MeCN) at a temperaturefrom about 40° C. to about 80° C.

In step b of Scheme 1, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine(5a) is reacted with an oxidant to yield3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). The oxidation may beconducted with potassium persulfate (K₂S₂O₈) in N,N-dimethylformamide(DMF) at about 80° C. to yield the product (5b). The oxidation may beconducted with about 0.3 equivalents to about 0.5 equivalents of acopper(I) salt, such as copper(I) sulfate (Cu₂SO₄), or a copper(I)halide, such as copper(I) chloride (CuCl), in the presence of an oxygensource, such as air, in a polar aprotic solvent such asN,N-dimethylformamide, N-methylpyrrolidinone (NMP) or 1,4-dioxane attemperatures from about 25° C. to about 100° C. This procedure resultsin higher yields and is more selective for3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b).

In step c of Scheme 1, 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) isnitrated with nitric (HNO₃) and sulfuric (H₂SO₄) acids to yield3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5c). The nitration may beconducted at about −10° C. to about 30° C.

In step d of Scheme 1, compound (5c) is reduced to yield3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d). For example, compound(5c) may be reduced with iron in acetic acid (AcOH). Compound (5c) mayalso be reduced with iron and ammonium chloride (NH₄Cl). Alternatively,this reduction may occur using other techniques in the art, for example,compound (5c) may be reduced using palladium on carbon in the presenceof hydrogen (H₂).

In step e of Scheme 1, 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d)is reacted with an activated carbonyl thioether, indicated asX¹C(═O)C₁-C₄-alkyl-S—R¹, to yield pesticidal thioether (3b). R¹ isselected from the group consisting of C₁-C₄-haloalkyl andC₁-C₄-alkyl-C₃-C₆-halocycloalkyl; preferably, R¹ is selected fromCH₂CH₂CF₃ or CH₂(2,2-difluorocyclopropyl). X¹ is selected from Cl,OC(═O)C₁-C₄ alkyl, or a group that forms an activated carboxylic acid.When X¹ is Cl or OC(═O)C₁-C₄ alkyl the reaction is conducted in thepresence of a base, preferably sodium bicarbonate, to yield pesticidalthioether (3b). Alternatively, the reaction may be accomplished whenX¹C(═O)C₁-C₄-alkyl-S—R¹ is an activated carboxylic acid activated bysuch reagents as 2,4,6-tripropyl-trioxatriphosphinane-2,4,-trioxide(T₃P), carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), preferably2,4,6-tripropyl-trioxatriphosphinane-2,4,-trioxide andcarbonyldiimidazole at temperatures from about 0° C. to about 80° C.;this reaction may also be facilitated with uronium or phosphoniumactivating groups such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU) orbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), in the presence of an amine base such as diisopropylethylamine(DIPEA) or triethylamine (TEA) in an polar aprotic solvent such asN,N-dimethylformamide, tetrahydrofuran (THF) or dichloromethane(CH₂Cl₂), at temperatures from about −10° C. to about 30° C. to formpesticidal thioether (3b). Activated carbonyl thioethers may be formedfrom carboxylic acids, indicated as X¹C(═O)C₁-C₄-alkyl-S—R¹, wherein X¹is OH, which may be prepared by reacting the corresponding esterthioether, indicated as X¹C(═O)C₁-C₄-alkyl-S—R¹, wherein X¹ isOC₁-C₄-alkyl, with a metal hydroxide such as lithium hydroxide (LiOH) ina polar solvent such as methanol or tetrahydrofuran.

Alternatively, X¹C(═O)C₁-C₄-alkyl-S—R¹, wherein X¹ is OH or OC₁-C₄-alkylmay be prepared by the photochemical free-radical coupling of3-mercaptopropionic acid and esters thereof with 3,3,3-trifluoropropenein the presence of 2,2-dimethoxy-2-phenylacetophenone initiator and longwavelength UV light in an inert organic solvent. While stoichiometricamounts of 3-mercaptopropionic acid or esters thereof and3,3,3-trifluoropropene are required, because of its low boiling point,excess 3,3,3-trifluoropropene is usually employed to compensate forroutine losses. From about 1 to about 10 mole percent initiator,2,2-dimethoxy-2-phenylacetophenone, is typically used, with about 5 molepercent being preferred. Long wavelength UV light is sometimes called“black light” and ranges from about 400 to about 365 nanometers. Thephotochemical coupling is conducted in an inert organic solvent. Typicalinert organic solvents must remain liquid to about −50° C., must remainrelatively inert to the free radical conditions and must dissolve thereactants at reaction temperatures. Preferred inert organic solvents arearomatic and aliphatic hydrocarbons like toluene. The temperature atwhich the reaction is conducted is not critical but usually is fromabout −50° C. to about 35° C. Lower temperatures, however, are betterfor increased selectivity. Initially, it is important to keep thetemperature below the boiling point of 3,3,3-trifluoropropene, i.e.,about −18 to about −16° C. In a typical reaction, the inert organicsolvent is cooled to less than about −50° C. and the3,3,3-trifluoropropene is bubbled into the solvent. The3-mercaptopropionic acid or esters thereof and2,2-dimethoxy-2-phenylacetophenone are added and a long wave function(366 nm) UVP lamp (4 watt) is turned on. After sufficient conversion of3-mercaptopropionic acid or esters thereof, the light is turned off andthe solvent removed.

3-((3,3,3-Trifluoropropyl)thio)propanoic acid may also be prepared bythe low temperature free-radical initiated coupling of3-mercaptopropionic acid with 3,3,3-trifluoropropene in the presence of2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70) initiator attemperatures of about −50° C. to about 40° C. in an inert organicsolvent. While stoichiometric amounts of 3-mercaptopropionic acid and3,3,3-trifluoropropene are required, because of its low boiling point,excess 3,3,3-trifluoropropene is usually employed to compensate forroutine losses. From about 1 to about 10 mole percent initiator, V-70,is typically used, with about 5 mole percent being preferred. The lowtemperature free-radical initiated coupling is conducted in an inertorganic solvent. Typical inert organic solvents must remain liquid toabout −50° C., must remain relatively inert to the free radicalconditions and must dissolve the reactants at reaction temperatures.Preferred inert organic solvents are toluene, ethyl acetate, andmethanol. The temperature at which the reaction is conducted from about−50° C. to about 40° C. Initially, it is important to keep thetemperature below the boiling point of 3,3,3-trifluoropropene, i.e.,about −18 to about −16° C. The solution is cooled to less than about−50° C. and the 3,3,3-trifluoropropene is transferred into the reactionmixture. After stirring at room temperature for 24 hours, the reactionmixture is heated to about 50° C. for about 1 hour to decompose anyremaining V-70 initiator followed by cooling and solvent removal.

In step f of Scheme 1, pesticidal thioether (3b) is alkylated with aR²—X² to yield pesticidal thioether (3c), wherein X² is a leaving group.The leaving group may be selected from halo, mesylate, or tosylate. R²is selected from C₁-C₄-alkyl, C₂-C₄-alkynyl, preferably, methyl, ethyl,and propargyl. R²—X² may be selected from methyl iodide, ethyl bromide,ethyl iodide, propargyl chloride, propargyl bromide, ethyl mesylate,propargyl mesylate, ethyl tosylate and propargyl tosylate. Thealkylation is conducted in the presence of an inorganic base,preferably, metal carbonates such as cesium carbonate (Cs₂CO₃), metalhydroxides, metal phosphates, metal hydrides, conducted in the presenceof a polar solvent, such as N,N-dimethylformamide at temperature fromabout 0° C. to about 80° C.

Alternatively, in step f of Scheme 1, the alkylation of pesticidalthioether (3b) may be conducted in the presence of a base such as sodiumhydride (NaH), in the presence of a polar aprotic solvent, such asN,N-dimethylformamide, tetrahydrofuran, hexamethylphosphoramide (HMPA),dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidinone or sulfolane, attemperatures from about 0° C. to about 30° C. It has been unexpectedlydiscovered that the use of sulfolane as solvent promotes the alkylationreaction over the competitive retro-Michael-type elimination of theC₁-C₄-alkyl-S—R¹ unit (see “CE-6”). It has been discovered that thecatalytic use of an iodide additive, such as potassium iodide (KI) ortetrabutylammonium iodide (TBAI) decreases the time necessary for thereaction to occur to about 24 hours.

In step g of Scheme 1, pesticidal thioether (3c) is oxidized withhydrogen peroxide (H₂O₂) in methanol to yield pesticidal sulfoxides(3d).

3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) in Scheme 1 may alternativelybe prepared by reacting 3-hydrazinopyridine dihydrochloride with methyl2-acetamidoacrylate to yieldN-(3-oxo-1-(pyridin-3-yl)pyrazolidin-4-yl)acetamide and subsequentchlorination/elimination as shown in Scheme 2, step a1.

Pesticidal thioether (5f) may be prepared from amine (5d) through thereaction pathway disclosed in Scheme 3. In step e1 of Scheme 3,3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (5d) is reacted withbetween about 1 equivalent and about 2 equivalents of 3-chloropropionylchloride in the presence of an inorganic base, preferably, metalcarbonates, metal hydroxides, metal phosphates, metal hydrides, morepreferably sodium bicarbonate (NaHCO₃) to yield3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropanamide(5e).

In step e2 of Scheme 3, compound (5e) reacts with HSR¹, wherein R¹ isdefined above, in the presence of an inorganic base, preferably, metalcarbonates, metal hydroxides, metal phosphates, metal hydrides, morepreferably, potassium hydroxide (KOH). This reaction may be conducted inthe presence of a polar solvent, preferably methanol, to yieldpesticidal thioether (5f).

3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may be prepared through thereaction pathway disclosed in Scheme 4. In step b1,3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with anoxidant to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). Theoxidation may be conducted with about 2 equivalents to about 4equivalents of potassium ferricyanide (K₂FeCN₆) in water in the presenceof about 2 equivalents to about 20 equivalents of an alkali metal base,such as potassium hydroxide, sodium hydroxide, or potassium carbonate,at temperatures ranging from about 50° C. to about 100° C. to yield theproduct (5b). About 1.5 equivalents to 3.0 equivalents potassiumpersulfate can be added as a terminal oxidant in this oxidation. Theamount of potassium ferricyanide can then be lowered to 1 equivalentwith improved yield.

3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may be prepared through thereaction pathway disclosed in Scheme 5. In step b2,3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with anoxidant to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). Theoxidation may be conducted with about 1.5 equivalents to about 10equivalents of manganese (IV) oxide (MnO₂) in a solvent such asacetonitrile, tert-amyl alcohol, or chlorobenzene, at temperaturesranging from about 60° C. to about 90° C. to yield the product (5b).Subsequent treatment of (5b) with a strong acid such as hydrochloricacid (HCl) may provide the salt of the product (5b).

3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through athree step, no isolation reaction sequence as disclosed in Scheme 6. Instep a2, 3-hydrazinopyridine dihydrochloride is reacted with methylacrylate in the presence of a base such as sodium methoxide or sodiumethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one, followed bychlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphorylchloride in a two-step process to yield 3-chloro-dihydropryazole (5a).In step b2, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) isreacted with manganese (IV) oxide to yield the product (5b). Subsequenttreatment of (5b) with an acid such as hydrochloric acid may provide thesalt of the product (5b). The first step may be conducted in a polarprotic solvent such as methanol or ethanol, at a temperature from about40° C. to about 80° C. The second step may be conducted in a solventsuch as chlorobenzene at a temperature from about 70° C. to about 90° C.The third step may be conducted in a solvent such as chlorobenzene at atemperature from about 70° C. to about 110° C.

3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through atwo-step reaction sequence as disclosed in Scheme 7. In step a3,3-hydrazinopyridine.dihydrochloride is reacted with3-ethoxyacrylonitrile or 3-methoxyacylonitrile in the presence of analkali metal C₁-C₄ alkoxide base such as sodium methoxide (NaOMe) orsodium ethoxide (NaOEt) to yield 3-(3-amino-1H-pyrazol-1-yl)pyridine(8a). In step b3, 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is reactedwith sodium nitrite (NaNO₂) in aqueous hydrochloric acid to provide thecorresponding diazonium salt followed by treatment of the diazonium saltwith copper chloride to yield the product (5b). The first step may beconducted in a C₁-C₄ aliphatic alcohol solvent such as methanol orethanol, at a temperature from about 25° C. to about 100° C. It is mostconvenient that the alkoxide base and the alcohol solvent be the same,for example, sodium ethoxide in ethanol. The second step may beconducted at a temperature from about 0° C. to about 25° C.

Alternatively, 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) may be preparedby the coupling of 3-bromopyridine and 3-aminopyrazole in awater-miscible polar aprotic organic solvent at a temperature of about75° C. to about 155° C. in the presence of a catalytic amount of copperchloride and a base. While stoichiometric amounts of 3-bromopyridine and3-aminopyrazole are required, it is often convenient to use an excess of3-aminopyrazole. An excess from about 10 mole percent to about 50 molepercent 3-aminopyrazole is preferred. The coupling is run in thepresence of about 5 mole percent to about 50 mole percent copperchloride, preferably from about 15 mole percent to about 30 mole percentcopper chloride. The copper chloride may be either copper (I) chlorideor copper (II) chloride. The coupling is also run in the presence of abase. While stoichiometric amounts of 3-bromopyridine and base arerequired, it is often convenient to use about a 1.5 fold to about a 2fold excess of base. Alkali metal carbonates are preferred bases. Thecoupling is performed in a water-miscible polar aprotic organic solvent.Polar aprotic organic solvents that are soluble in water includenitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide,and amides such as N-methylpyrrolidinone, N,N-dimethylformamide andN,N-dimethylacetamide. N,N-Dimethylformamide is particularly preferred.

3-(3-Amino-1H-pyrazol-1-yl)pyridine (8a) may also be prepared through atwo-step reaction sequence as disclosed in Scheme 8. In step a4,3-hydrazinopyridine dihydrochloride is treated with acrylonitrile in aC₁-C₄ aliphatic alcohol at a temperature of about 25° C. to about 100°C. in the presence of an alkali metal C₁-C₄ alkoxide to provide1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a). Whilestoichiometric amounts of 3-hydrazinopyridine dihydrochloride andacrylonitrile are required, it is often convenient to use about a 1.5fold to about a 2 fold excess of acrylonitrile. The cyclization is runin the presence of an alkali metal C₁-C₄ alkoxide base. It is oftenconvenient to use about a 2 fold to about a 5 fold excess of base. Thecyclization is performed in a C₁-C₄ aliphatic alcohol. It is mostconvenient that the alkoxide base and the alcohol solvent be the same,for example, sodium ethoxide in ethanol. In step b4,1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a) is treated with anoxidant in an organic solvent at a temperature of about 25° C. to about100° C. to provide 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a). Suitableoxidants include manganese (IV) oxide, potassium ferricyanide (III),copper (I) chloride in the presence of oxygen, and iron (III) chloridein the presence of oxygen. Manganese (IV) oxide is preferred. It isoften convenient to use about a 1.5 fold to about a 10 fold excess ofoxidant. The oxidation is performed in a solvent that is inert to theoxidant. Suitable solvents include nitriles such as acetonitrile orhalocarbons such as dichloromethane or chlorobenzene. With manganese(IV) oxide as the oxidant, acetonitrile is a preferred solvent.

In step a of Scheme 9, 3-hydrazinopyridine.dihydrochloride is treatedwith a di-C₁-C₄ alkyl maleate such as diethyl maleate in a C₁-C₄aliphatic alcohol at a temperature of about 25° C. to about 100° C. inthe presence of an alkali metal C₁-C₄ alkoxide to provide pyrazolidinecarboxylate (10a). While stoichiometric amounts of3-hydrazinopyridine.dihydrochloride and di-C₁-C₄ alkyl maleate arerequired, it is often convenient to use about a 1.5 fold to about a 2fold excess of di-C₁-C₄ alkyl maleate. The cyclization is run in thepresence of an alkali metal C₁-C₄ alkoxide base such as sodium ethoxide.It is often convenient to use about a 2 fold to about a 5 fold excess ofbase. The cyclization is performed in a C₁-C₄ aliphatic alcohol such asethanol. It is most convenient that the alkoxide base and the alcoholsolvent be the same, for example, sodium ethoxide in ethanol.

In step b of Scheme 9, the pyrazolidine carboxylate (10a) may be treatedwith a chlorinating reagent in an inert organic solvent at a temperatureof about 25° C. to about 100° C. to provide chlorinated dihydropyrazolecarboxylate (10b). Suitable chlorinating reagents include phosphoryltrichloride and phosphorus pentachloride. Phosphoryl chloride ispreferred. It is often convenient to use about a 1.1 fold to about a 10fold excess of the chlorinating reagent. The chlorination is performedin an organic solvent that is inert to the chlorinating reagent.Suitable solvents include nitriles such as acetonitrile. With phosphoryltrichloride as the chlorinating reagent, acetonitrile is a preferredsolvent.

In step c of Scheme 9, chlorinated dihydropyrazole carboxylate (10b) maytreated with an oxidant in an organic solvent at a temperature of about25° C. to about 100° C. to provide chlorinated pyrazole carboxylate(10c). Suitable oxidants include manganese (IV) oxide and sodiumpersulfate/sulfuric acid. It is often convenient to use about a 1.5 foldto about a 15 fold excess of oxidant. The oxidation is performed in anorganic solvent that is inert to the oxidant. Suitable solvents includenitriles such as acetonitrile. With manganese (IV) oxide (MnO₂) orsodium persulfate/sulfuric acid as the oxidant, acetonitrile is apreferred solvent.

In step d of Scheme 9, chlorinated pyrazole carboxylate (10c) may thenbe converted to the desired3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(6e) by treatment in aqueous hydrochloric acid at a temperature of about25° C. to about 100° C. While stoichiometric amounts of reagents arerequired, it is often convenient to use an excess of reagents withrespect to the chlorinated pyrazole carboxylate. Thus, aqueoushydrochloric acid is used in large excess as the reaction medium.Alternatively, chlorinated pyrazole carboxylates may be saponified inthe presence of an inorganic base, preferably metal hydroxides or theirhydrates such as lithium hydroxide hydrate (LiOH.H₂O) in water and apolar solvent such as dioxane at temperatures from about 0° C. to about30° C. to yield 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid(6e).

In step e of Scheme 9,3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(6e) is decarboxylated in the presence of copper (II) oxide in polarsolvents such as N,N-dimethylformamide at temperatures from about 80° C.to about 140° C. to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). Itwas surprisingly discovered that this decarboxylation only occurs in thepresence of copper (II) oxide. Several known decarboxylation agents fromthe literature such as, for example, hydrochloric acid (See alternatesynthetic route, Example 17), sulfuric acid, and palladium (II)trifluoroacetate/trifluoroacetic acid (See “CE-7”) did not yield thedesired product.

EXAMPLES

The following examples are presented to better illustrate the processesof the present application.

Example 1 3-(3-Chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a)

A 500 mL, 3-neck round bottom flask was charged with methyl acrylate(18.9 g, 220 mmol) and ethanol (110 mL). 3-hydrazinopyridinedihydrochloride (20.0 g, 110 mmol) was added, followed by sodiumethoxide (29.9 g, 439 mmol) and the reaction was stirred at 60° C. for 6hours, at which point thin layer chromatography (TLC) analysis [Eluent:10% methanol/dichloromethane] indicated that the starting material haddisappeared and a major product had formed: ESIMS m/z 164 ([M+H]⁺). Thereaction was allowed to cool to 20° C. and concentrated to afford ayellow solid. The resulting solid was charged with phosphoryl chloride(100 g, 654 mmol). The reaction was stirred at 60° C. for 3 hours, atwhich point a sample of the reaction mixture was diluted with water andbasified with 15 wt % sodium hydroxide (NaOH) solution. The resultingsolution was extracted with ethyl acetate (EtOAc) and the organic layerwas analyzed by thin layer chromatography [Eluent: ethyl acetate], whichindicated that the reaction was complete.

The reaction mixture was slowly quenched into water (400 mL) at <30° C.and the resulting solution was basified with 50 wt % sodium hydroxidesolution to pH>10. The resulting solution was extracted with ethylacetate (3×200 mL) and the organic layers were combined and concentratedto dryness. The residue was purified by flash column chromatographyusing 50-80% ethyl acetate/hexanes as eluent. The fractions containingpure product were concentrated to dryness and the resulting yellow solidwas dried under vacuum to afford the desired product as a yellow solid(11.3 g, 66%): mp 66-68° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=2.8Hz, 1H), 8.07 (dd, J=4.5, 1.5 Hz, 1H), 7.32 (ddd, J=8.4, 2.9, 1.6 Hz,1H), 7.26 (dd, J=8.4, 4.5 Hz, 1H), 3.93 (t, J=10.2 Hz, 2H), 3.23 (t,J=10.2 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 144.37, 142.05, 140.50,134.64, 123.65, 119.31, 49.63, 36.90; EIMS m/z 181 ([M]⁺).

Example 2 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

A 100 mL, 3-neck round bottom flask was charged with3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (3.0 g) andN,N-dimethylformamide (15 mL). potassium persulfate (6.70 g, 24.8 mmol)was added and the reaction was heated to 80° C. for 3 hours. An exothermat about 110° C. was observed. It was allowed to cool to 80° C. andstirred at 80° C. for 3 hours, at which point a sample was diluted withwater and basified with 50 wt % sodium hydroxide solution and extractedwith ethyl acetate. The organic layer was analyzed by thin layerchromatography [Eluent: ethyl acetate], which showed that the desiredproduct was formed as the major product, along with a trace of startingmaterial and some minor impurities. The reaction mixture was cooled to20° C. and diluted with water (50 mL). It was basified with 50% sodiumhydroxide and extracted with ethyl acetate (4×30 mL). The organic layerswere combined, concentrated to dryness, and purified by flash columnchromatography using 30% ethyl acetate/hexanes as eluent. The purefractions were concentrated to dryness to afford a white solid (1.60 g,54%): mp 104-106° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=27 Hz, 1H),8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91(d, J=2.6 Hz, 1H), 7.47-7.34 (M, 1H), 6.45 (d, J=2.6 Hz, 1H); ¹³C NMR(101 MHz, CDCl₃) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41,124.01, 108.08; EIMS m/z 179 ([M]⁺).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

Crude 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (54.1 g, 232mmol, 77.8% purity) was introduced into a 3 L three-neck round bottomflask. Water (530 mL) was then added. The mixture was heated to 60° C.and a potassium hydroxide solution (165 g, 2940 mmol) in water (500 mL)was added. The dark brown mixture was heated to 90° C. A potassiumferricyanide solution (253 g, 768 mmol) in water (700 mL) was addedslowly over 30 minutes leading to brown-red mixture. The mixture wasstirred at 90° C. for another 1.5 hours. The reaction mixture was cooledto below 45° C. and filtered. The filter cake was washed with water (300mL) affording crude product as a brown solid. The crude product was thendissolved in acetonitrile (400 mL) and filtered. The organic filtratewas dried and concentrated to afford the title product as a brown solid(28.8 g, 69%, 94% purity).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

3-(3-Chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (362 mg, 2.0 mol) wasintroduced into a 25 mL vial. Potassium hydroxide solution (658 mg, 85%pure) in water (H₂O) (4.0 mL) was added and the mixture was heated to60° C. Potassium ferricyanide solution (656 mg in 1.0 mL water) wasadded over 15 minutes leading to brown mixture. The mixture was stirredat 62° C. for another 15 minutes. Potassium persulfate solution (270 mg,1.0 mmol, 0.5 eq.) in water (1.0 mL) was added in one portion. Themixture was stirred at 60° C. and monitored by LC. Additional twoportions of potassium persulfate solution (270 mg, 1.0 mmol, 0.5 eq.) inwater (1.0 mL) was added at 1.5 hours and at 2.5 hours. The reactionmixture was stirred for a total 4.5 hours and LC indicated 88.0%conversion. The mixture was then stirred at 75° C. for 1.5 hours and LCindicated >90% conversion. After filtration, the filter cake was washedwith water (10 mL) affording crude product as a pale brown solid. Thecrude product was then washed with acetonitrile (2×15 mL). The organicfiltrate was dried and concentrated to afford desired product as lightbrown solid (328 mg, 91.6%, 94.0% pure by LC).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (1.09g, 6.00 mmol) in dry N,N-dimethylformamide (6.0 mL) in a 25 mL roundbottom flask was added copper(I) chloride (0.178 g, 1.80 mmol) leadingto a green suspension. Dried air was bubbled through the mixture. Theresultant dark green mixture was stirred at 85° C. for 16 hours. Themixture was then cooled down and dispersed into water (20 mL) and ethylacetate (20 mL). The mixture was filtered through a pad of Celite® andwashed thoroughly with ethyl acetate (4×20 mL). Aqueous layer wasextracted with ethyl acetate (4×20 mL). The combined organic extractswere dried over anhydrous sodium sulfate (Na₂SO₄) and concentrated toafford crude product (0.582 g, 51%).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

To a solution of 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole (1.82g, 10.0 mmol) in acetonitrile (20 mL) was added manganese (IV) oxide(4.35 g, 50 mmol) (Aldrich activated). The mixture was heated at 55° C.for 10 hours. The mixture was filtered hot through Celite®, and washedwith acetonitrile (2×5 mL). The light amber liquid was concentrated togive a light pink solid (1.99 g). This solid was dried at 55° C. with anitrogen purge to give a solid (1.92 g, 83%, LC internal standardanalysis indicated a purity of 77.6 wt %). A portion of the solid (1.26g) was dissolved in hot 10% water in ethanol (6 mL). The solution wasfiltered hot through a sintered glass funnel to remove cloudiness. Thissolution was scratched and cooled overnight in a refrigerator. The solidwas filtered and dried at 55° C. with a nitrogen purge to give the titlecompound as an off-white solid (0.512 g, mp 102×104° C.).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

To a solution of 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole (0.182g, 1.00 mmol) in tert-amyl alcohol (2 mL) was added manganese (IV) oxide(0.870 g, 10 mmol) (Carus black). The mixture was heated at 80° C. for19 hours. LC analysis indicated complete conversion to product. Thereaction was not worked up.

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

To a three-neck round bottomed flask (25 mL) was introduced3-(3-amino-1H-pyrazol-1-yl)pyridine (0.480 g, 3.00 mmol) andconcentrated hydrochloric acid (4.6 mL). The vigorously stirred mixturewas cooled to −5° C. using sodium chloride (NaCl) ice-bath. Sodiumnitrite (0.269 g, 3.90 mmol) in water (1.3 mL) was added dropwise over40 minutes while maintaining the temperature at −5° C. The resultantdark orange mixture was stirred for 1 hour between −5° C. and ˜0° C. andthen added dropwise into a suspension of copper(I) chloride (0.475 g,4.80 mmol) in chloroform (CHCl₃, 4.8 mL) at 25° C. over 15 minutes. Thedark green slurry was stirred at room temperature for 1 hour. Water (10mL) and chloroform (10 mL) was added to the mixture leading to a darkgreen solution. The acidic aqueous solution was neutralized by sodiumhydroxide (50% in water) to pH 8 and extracted with chloroform (2×10 mL)and ethyl acetate (3×20 mL). The combined organic extracts were driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford crude product as a yellow solid (0.476 g). LC assay usingdi-n-propyl phthalate as internal standard indicated 73.7% purity (0.351g, 65%): ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.8 Hz, 1H), 8.57 (dd,J=4.8, 1.2 Hz, 1H), 8.03 (ddd, J=8.4, 2.8, 1.6 Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.41 (ddd, J=8.4, 4.8, 0.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H);EIMS m/z 179 ([M]⁺); HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobilephase: A=water (0.1% formic acid), B=acetonitrile (0.01% formic acid);Gradient from 5 to 100% acetonitrile over 15 minutes; flow: 1.0mL/minute): t_(R)=6.28 minutes.

Example 2a 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) hydrochloride

A mixture of 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole (0.182 g,1.00 mmol) and manganese (IV) oxide (0.870 g, 10.0 mmol) (Carus black)in chlorobenzene (2 mL) was heated at 80° C. for 24 hours. The mixturewas allowed to cool to room temperature, filtered through Celite®, andthe wetcake was rinsed with chlorobenzene (2 mL). The lightly tintedsolution was acidified with hydrochloric acid (4 M in 1,4-dioxane) to˜pH 1.5 to give a thick, white mixture. After stirring in an ice-bathfor 30 minutes, the mixture was filtered through a sintered glass funneland rinsed with cold chlorobenzene (2 mL). The solids (0.380 g) wereallowed to air-dry in a hood overnight to give the title compound as anoff-white solid (0.140 g, 64%, LC internal standard analysis indicated apurity of 98.7 wt %): mp 229-237° C.; ¹H NMR (DMSO-d₆) δ 11.11 (bs, 1H),9.27 (d, J=2.4 Hz, 1H), 8.82 (d, J=2.7 Hz, 1H), 8.71 (dd, J=5.1, 1.2 Hz,1H), 8.61 (ddd, J=8.5, 2.5, 1.2 Hz, 1H), 7.89 (dd, J=8.5, 5.1 Hz, 1H),6.79 (d, J=2.7 Hz, 1H).

Alternate Synthetic Route to: 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)hydrochloride Step 1. 1-(Pyridin-3-yl)pyrazolidin-3-one

In a four-neck round bottomed flask (250 mL) which contained3-hydrazinopyridine dihydrochloride (18.2 g, 0.100 mol) was added sodiumethoxide (21 wt % in ethanol, 107 g, 0.330 mol). The temperature of theslurry rose to 33° C. over 5 minutes. The mixture was stirred at roomtemperature for 1.25 hours. To the light red tinted slurry was addedmethyl acrylate (18.0 mL, 0.200 mol) over 10 minutes, with thetemperature rising from 25° C. to 35° C. The color of the slurry changedfrom light red to brown/green. The mixture was heated at 55° C. for 3hours. After stirring at room temperature overnight, the mixture wasneutralized to pH˜7 with hydrochloric acid (4 M in 1,4-dioxane, 32.6 g,0.130 mol). The dark gray slurry was concentrated to a dark, paste likesolid.

Step 2. 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a)

To the paste-like solid obtained from Step 1 in a 4-neck round bottomedflask (500 mL) was added chlorobenzene (120 mL). Phosphoryl chloride(10.2 mL, 0.110 mol) was added dropwise to the thick mixture over 10minutes. The temperature of the mixture went from 22° C. to 27° C. Theslurry was heated at 80° C. for 1 hour. The mixture was cooled to 25°C., water (120 mL) was added to dissolve the solids, and the temperaturerose to 28° C. The two phase mixture was brought to pH˜12 with sodiumhydroxide (50% in water, 42.8 g) using an ice-bath cooling to keep thetemperature below 40° C. After cooling to 30° C., the mixture wastransferred to a separatory funnel. The phases separated rapidly, andthe bottom aqueous layer (containing some suspended solids) was removedfrom the dark organic phase. Attempted re-extraction of the aqueousphase with chlorobenzene (30 mL) resulted in an emulsion with solidspresent. The mixture was filtered through Celite®, the phases allowed tosettle, and the organics added to the above organic phase to give asolution of the title compound as a dark amber liquid containing a smallamount of fine solids (319 g, LC internal standard analysis indicated4.3 wt % (75.4 mmol) 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole inthe solution, for an in-pot yield of 75% starting from3-hydrazinopyridine).

Step 3 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) hydrochloride

To the above solution in a round bottomed flask (500 mL) was addedmanganese (IV) oxide (70.0 g, 0.800 mol) and the mixture heated at 80°C. for 17 hours. The temperature was increased to 100° C. and heated foranother 18 hours. The mixture was allowed to cool to 50° C. and filteredthrough Celite®. The amber solution was acidified with hydrochloric acid(4 M in 1,4-dioxane, 21.5 g) to pH˜1.5. The thick fine precipitate wasstirred at room temperature for 0.5 hours, filtered (slow, cracking ofcake), and rinsed with chlorobenzene. The paste-like solid (48.99 g) wasair dried in a hood overnight, the hard solid crushed with a spatula,and further dried at 55° C. with a nitrogen purge to give the titlecompound as a light tan solid (15.2 g, LC internal standard analysisindicated a purity of 91.9 wt %, for a 64.7% isolated yield of3-(3-chloro-1H-pyrazol-1-yl)-pyridine hydrochloride starting from3-hydrazinopyridine dihydrochloride).

Example 3 3-(3-Chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5c)

To a 100 mL, round bottom flask was charged3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) andconcentrated sulfuric acid (4 mL). This suspension was cooled to 5° C.and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by addingthe concentrated sulfuric acid to a stirring and cooling solution of thenitric acid) was added dropwise at a rate such that the internaltemperature was maintained <15° C. The reaction was allowed to warm to20° C. and stirred for 18 hours. A sample of the reaction mixture wascarefully diluted into water, basified with 50 wt % sodium hydroxide andextracted with ethyl acetate. Analysis of the organic layer indicatedthat the reaction was essentially complete. The reaction mixture wascarefully added to ice cold water (100 mL) at <20° C. It was basifiedwith 50% sodium hydroxide at <20° C. The resulting light yellowsuspension was stirred for 2 hours and filtered. The filter cake wasrinsed with water (3×20 mL) and dried to afford an off-white solid (2.5g, quantitative): mp 141-143° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s,1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33 (ddd, J=8.4, 2.8, 1.4Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆)δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76, 127.22, 124.31; EIMSm/z 224 ([M]⁺).

Example 4 3-(3-Chloro-4-amino-1H-pyrazol-1-yl)pyridine (5d)

To a 100 mL, 3-neck round bottom flask was charged3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2.40 g, 10.7 mmol), aceticacid (4 mL), ethanol (4.8 mL) and water (4.8 mL). The mixture was cooledto 5° C. and iron powder (2.98 g, 53.4 mmol) was added portionwise over˜15 minutes. The reaction was allowed to stir at 20° C. for 18 hours anddiluted to 50 mL with water. It was filtered through Celite® and thefiltrate was carefully basified with 50 wt % sodium hydroxide solution.The resulting suspension was filtered through Celite® and the filtratewas extracted with ethyl acetate (3×20 mL). The organic layers werecombined and dried over sodium sulfate and concentrated to dryness toafford a tan colored solid, which was further dried under vacuum for 18hours (2.20 g, quantitative): mp 145-147° C.; ¹H NMR (400 MHz, DMSO-d₆)δ 8.95 (dd, J=2.6, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.08 (ddd,J=8.4, 2.7, 1.4 Hz, 1H), 7.91 (s, 1H), 7.49 (ddd, J=8.3, 4.7, 0.8 Hz,1H), 4.43 (s, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 146.35, 138.53, 135.72,132.09, 130.09, 124.29, 124.11, 114.09; EIMS m/z 194 ([M]⁺).

Alternate Synthetic Route to:3-(3-Chloro-4-amino-1H-pyrazol-1-yl)pyridine (5d)

In a 250 mL 3-neck round bottom flask was added3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5.00 g, 21.8 mmol),ethanol (80 mL), water (40 mL), and ammonium chloride (5.84 g, 109mmol). The suspension was stirred under nitrogen stream for 5 minutesthen iron powder (4.87 g, 87.2 mmol) added. The reaction mixture washeated to reflux (˜80° C.) and held there for 4 hours. After 4 hours areaction aliquot taken showed by HPLC analysis the reaction had gone tofull conversion. Ethyl acetate (120 mL) and Celite® (10 g) were added tothe reaction mixture and let stir for 10 minutes. The black coloredsuspension was then filtered via a Celite® pad and the pad rinsed withethyl acetate (80 mL). The reaction mixture was washed with saturatedsodium bicarbonate (30 mL) and the organic layer was assayed. The assaygave (4.19 g, 99%) of product. The organic solvent was removed in vacuoto give a brown colored crude solid that was used without furtherpurification.

Example 5N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 5.5)

A 100-mL, three-neck round bottom flask was charged with3-chloro-(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethylacetate (10 mL). Sodium bicarbonate (1.08 g, 12.9 mmol) was added,followed by dropwise addition of3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (1.36 g, 6.17 mmol) at<20° C. The reaction was stirred at 20° C. for 2 hours, at which pointthin layer chromatography analysis [Eluent: ethyl acetate] indicatedthat the reaction was complete. The reaction was diluted with water (50mL) and the layers separated. The aqueous layer was extracted with ethylacetate (20 mL) and the combined organic layers were concentrated todryness to afford a light brown oil. The residue was purified by flashcolumn chromatography using 30-60% ethyl acetate/hexanes. The fractionscontaining pure product were concentrated to dryness to afford a whitesolid (1.40 g, 72%): mp 99-102° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s,1H), 9.05 (d, J=2.7 Hz, 1H), 8.86 (s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H),8.21 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86(t, J=7.3 Hz, 2H), 2.74 (td, J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7,9.7, 7.4 Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 169.32, 147.49, 139.44,135.47, 133.40, 126.60 (q, J=296 Hz), 125.49, 124.23, 122.30, 120.00,35.18, 33.42 (q, J=27.2 Hz), 26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378([M]⁺).

Example 6 3-((3,3,3-Trifluoropropyl)thio)propanoic acid

A 100 mL, 3-neck round bottom flask was charged with 3-bromopropanoicacid (500 mg, 3.27 mmol) and methanol (10 mL), potassium hydroxide (403mg, 7.19 mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol(468 mg, 3.60 mmol). The mixture was heated at 50° C. for 4 hours, afterwhich it was acidified with 2 N hydrochloric acid and extracted withmethyl tert-butylether (MTBE, 2×10 mL). The organic layer wasconcentrated to dryness to afford a light yellow oil (580 mg, 88%): ¹HNMR (400 MHz, CDCl₃) δ 2.83 (td, J=7.1, 0.9 Hz, 2H), 2.78-2.64 (m, 4H),2.48-2.32 (m, 2H).

Alternate Synthetic Route to: 3-((3,3,3-Trifluoropropyl)thio)propanoicacid

A 100 mL stainless steel Parr reactor was charged withazobisisobutyronitrile (AIBN, 0.231 g, 1.41 mmol), toluene (45 mL),3-mercaptopropionic acid (3.40 g, 32.0 mmol), and octanophenone (526.2mg) as an internal standard, and was purged and pressure checked withnitrogen (N₂). The reactor was cooled with dry ice and the3,3,3-trifluoropropene (3.1 g, 32.3 mmol) was condensed into thereactor. The ice bath was removed and the reactor heated to 60° C. andstirred for 27 hours. The internal yield of the reaction was determinedto be 80% by use of the octanophenone internal standard. The pressurewas released and the crude mixture removed from the reactor. The mixturewas concentrated by rotary evaporation and 50 mL of 10% sodium hydroxidewas added. The solution was washed with methyl tert-butylether (50 mL)then acidified to pH˜1 with 6 N hydrochloric acid. The product wasextracted with 100 mL methyl tert-butylether, dried over magnesiumsulfate (MgSO₄), filtered, and concentrated to give the crude titledcompound as an oil (5.34 g, 26.4 mmol, 83%): ¹H NMR (400 MHz, CDCl₃) δ2.83 (td, J=7.1, 0.9 Hz, 2H), 2.76-2.64 (m, 4H), 2.47-2.30 (m, 2H); ¹³CNMR (101 MHz, CDCl₃) δ 177.68, 125.91 (q, J=277.1 Hz), 34.58 (q, J=28.8Hz), 34.39, 26.63, 24.09 (q, J=3.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ−66.49.

Alternate Synthetic Route to: 3-((3,3,3-Trifluoropropyl)thio)propanoicacid

A 250 mL three-neck round bottomed flask was charged with toluene (81mL) and cooled to <−50° C. with a dry ice/acetone bath.3,3,3-Trifluoropropene (10.28 g, 107.0 mmol) was bubbled into thesolvent and the ice bath was removed. 3-Mercaptopropionic acid (9.200 g,86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol)was added and the long wave light (366 nm, 4 watt UVP lamp) was turnedon (Starting temperature: −24° C.). The reaction reached a temperatureof 27.5° C. due to heat from the lamp. The reaction was stirred with theblack light on for 4 hours. After 4 hours the black light was turned offand the reaction concentrated by rotary evaporation (41° C., 6 mm Hg)giving a pale yellow oil (18.09 g, 51:1 linear:branched isomer, 90 wt %linear isomer by GC internal standard assay, 16.26 g active, 93%). Thecrude material was dissolved in 10% sodium hydroxide w/w (37.35 g) andwas washed with toluene (30 mL) to remove non-polar impurities. Theaqueous layer was acidified to pH˜2-3 with hydrochloric acid (2 N, 47.81g) and was extracted with toluene (50 mL). The organic layer was washedwith water (40 mL) and dried over magnesium sulfate, filtered, andconcentrated by rotary evaporation giving a pale yellow oil (14.15 g,34:1 linear:branched isomer, 94 wt % linear isomer by GC internalstandard assay, 13.26 g active, 76%).

Alternate Synthetic Route to: 3-((3,3,3-Trifluoropropyl)thio)propanoicacid

A 100 mL stainless steel Parr reactor was charged with3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g), and2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76mmol) and the reactor was cooled with a dry ice/acetone bath, purgedwith nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.20 g,33.3 mmol) was added via transfer cylinder and the reaction was allowedto warm to 20° C. After 24 hours, the reaction was heated to 50° C. for1 hour to decompose any remaining V-70 initiator. The reaction wasallowed to cool to room temperature. The solution was concentrated byrotary evaporation to provide the title compound (6.80 g, 77.5 wt %linear isomer by GC internal standard assay, 5.27 g active, 76%, 200:1linear:branched by GC, 40:1 linear:branched by fluorine NMR).

Example 7 Methyl-3-((3,3,3-trifluoropropyl)thio)propionate

A 100 mL stainless steel Parr reactor was charged withazobisisobutyronitrile (0.465 g, 2.83 mmol), toluene (60 mL) andmethyl-3-mercaptopropionate (7.40 g, 61.6 mmol) and was purged andpressure checked with nitrogen. The reactor was cooled with dry ice andthe 3,3,3-trifluopropopene (5.7 g, 59.3 mmol) was condensed into thereactor. The ice bath was removed and the reactor heated to 60° C. andstirred to 24 hours. The heat was turned off and the reaction left atroom temperature (about 22° C.) overnight. The mixture was removed fromthe reactor and concentrated to a yellow liquid. The liquid wasdistilled by vacuum distillation (2 Torr, 85° C.) and three fractionswere collected: fraction 1 (1.3 g, 6.01 mmol, 10%, 70.9 area % by GC),fraction 2 (3.7 g, 17.1 mmol, 29%, 87 area % by GC), and fraction 3 (4.9g, 22.7 mmol, 38%, 90.6 area % by GC): ¹H NMR (400 MHz, CDCl₃) δ 3.71(s, 3H), 2.82, (td, J=7.3, 0.7 Hz, 2H), 2.75-2.68 (m, 2H), 2.63 (td,J=7.2, 0.6 Hz, 2H), 2.47-2.31 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ172.04, 125.93 (q, J=277.2 Hz), 51.86, 34.68 (q, J=28.6 Hz), 34.39,27.06, 24.11 (q, J=3.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.53.

Alternate Synthetic Route to:Methyl-3-((3,3,3-trifluoropropyl)thio)propionate

A 500 mL three-neck round bottomed flask was charged with toluene (200mL) and cooled to <−50° C. with a dry ice/acetone bath.3,3,3-Trifluoropropene (21.8 g, 227 mmol) was condensed into thereaction by bubbling the gas through the cooled solvent and the ice bathwas removed. Methyl 3-mercaptopropionate (26.8 g, 223 mmol) and2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and aUVP lamp (4 watt) that was placed within 2 centimeters of the glass wallwas turned on to the long wave function (366 nanometers). The reactionreached 35° C. due to heat from the lamp. After 4 hours, all of thetrifluoropropene was either consumed or boiled out of the reaction. Thelight was turned off and the reaction stirred at room temperatureovernight. After 22 hours, more trifluoropropene (3.1 g) was bubbledthrough the mixture at room temperature and the light was turned on foran additional 2 hours. The reaction had reached 93% conversion, so nomore trifluoropropene was added. The light was turned off and themixture concentrated on the rotovap (40° C., 20 torr) giving a yellowliquid (45.7 g, 21.3:1 linear:branched isomer, 75 wt % pure linearisomer determined by a GC internal standard assay, 34.3 g active, 71% inpot yield).

Alternate Synthetic Route to:Methyl-3-((3,3,3-trifluoropropyl)thio)propionate

A 100 mL stainless steel Parr reactor was charged with methyl3-mercaptopropionate (4.15 g, 34.5 mmol), toluene (30.3 g), and2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.531 g, 1.72mmol) and the reactor was cooled with a dry ice/acetone bath, purgedwith nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.40 g,35.4 mmol) was added via transfer cylinder and the reaction was allowedto warm to 20° C. After 23 hours the reaction was heated to 50° C. for 1hour to decompose any remaining V-70 initiator. The reaction was allowedto cool to room temperature. The solution was concentrated to providethe title compound (7.01 g, 66%, 70.3 wt % linear isomer by GC internalstandard assay, 4.93 g active, 66%, 24:1 linear:branched by GC, 18:1linear:branched by fluorine NMR).

Example 8N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 8.5)

A 100 mL, 3-neck round bottom flask, equipped with mechanical stirrer,temperature probe and nitrogen inlet was charged with cesium carbonate(654 mg, 2.01 mmol),N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(380 mg, 1.00 mmol) and N,N-dimethylformamide (5 mL). Iodoethane (0.0890mL, 1.10 mmol) was added dropwise. The reaction was stirred at 40° C.for 2 hours, at which point thin layer chromatography analysis (Eluent:ethyl acetate) indicated that only a trace of starting materialremained. The reaction mixture was cooled to 20° C. and water (20 mL)was added. It was extracted with ethyl acetate (2×20 mL) and thecombined organic layer was concentrated to dryness at <40° C. Theresidue was purified by flash column chromatography using 0-100% ethylacetate/hexanes as eluent. The fractions containing pure product wereconcentrated to dryness to afford a colorless oil (270 mg, 66%): mp79-81° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.11 (d, J=2.7 Hz, 1H), 8.97 (s,1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.8, 1.4 Hz, 1H),7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.62 (q, J=7.1 Hz, 2H), 2.75 (t,J=7.0 Hz, 2H), 2.66-2.57 (m 2H), 2.57-2.44 (m, 2H), 2.41 (t, J=7.0 Hz,2H), 1.08 (t, J=7.1 Hz, 3H); EIMS m/z 406 ([M]⁺).

Alternate Synthetic Route to:N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 8.5)

To 3-neck round bottomed flask (50 mL) was added sodium hydride (60% inoil, 0.130 g, 3.28 mmol) and sulfolane (16 mL). The gray suspension wasstirred for 5 minutes thenN-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(1.20 g, 3.16 mmol) dissolved in sulfolane (25 mL) was slowly addeddropwise over 5 minutes. The mixture became a light gray suspensionafter 3 minutes and was allowed to stir for 5 minutes after which timeethyl bromide (0.800 mL, 10.7 mmol) and potassium iodide (0.120 g, 0.720mmol) were added sequentially. The cloudy suspension was then allowed tostir at room temperature. The reaction was quenched after 6 hours bybeing poured drop-wise into cooled ammonium formate/acetonitrilesolution (30 mL). The resulting orange colored solution was stirred andtetrahydrofuran (40 mL) was added. The mixture was assayed, usingoctanophenone as a standard, and found to contain 1.09 g (85%) of thedesired product with a selectivity versus the retro-Michael-likedecomposition product of 97:3.

Example 9N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)sulfoxo)propanamide(Compound 9.5)

N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (57.4 g, 141 mmol) was stirred in methanol (180 mL). To theresulting solution was added hydrogen peroxide (43.2 mL, 423 mmol)dropwise using a syringe. The solution was stirred at room temperaturefor 6 hours, at which point LCMS analysis indicated that the startingmaterial was consumed. The mixture was poured into dichloromethane (360mL) and washed with aqueous sodium carbonate (Na₂CO₃). The organic layerwas dried over sodium sulfate and concentrated to provide a thick yellowoil. The crude product was purified by flash column chromatography using0-10% methanol/ethyl acetate as eluent and the pure fractions werecombined and concentrated to afford the desired product as an oil (42.6g, 68%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (dd, J=2.8, 0.7 Hz, 1H), 8.98(s, 1H), 8.60 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (ddd, J=8.4, 2.7, 1.4 Hz,1H), 7.60 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 3.61 (q, J=7.4, 7.0 Hz, 2H),3.20-2.97 (m, 2H), 2.95-2.78 (m, 2H), 2.76-2.57 (m, 2H), 2.58-2.45 (m,2H), 1.09 (t, J=7.1 Hz, 3H); ESIMS m/z 423 ([M+H]⁺).

Example 10 3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b)

A 250 mL, 3-neck round bottom flask was charged with methyl2-acetamidoacrylate (4.91 g, 34.3 mmol) and ethanol (40 mL).3-Hydrazinopyridine dihydrochloride (5 g, 27.5 mmol) was added, followedby sodium ethoxide (7.48 g, 110 mmol) and the reaction was stirred at60° C. for 6 hours, at which point thin layer chromatography analysis[Eluent: 10% methanol/dichloromethane] indicated that the startingmaterial had disappeared and a major product had formed: ESIMS m/z 221([M+H]⁺). The reaction was allowed to cool to room temperature andconcentrated to afford a yellow solid. The resulting solid was slowlycharged with phosphoryl chloride (29.2 g, 191 mmol). The reaction wasstirred at 60° C. for 3 hours, at which point a sample of the reactionmixture was diluted with water and basified with 50 wt % sodiumhydroxide solution. The resulting solution was extracted with ethylacetate and the organic layer was analyzed by thin layer chromatography[Eluent: ethyl acetate], which indicated that the reaction was complete.The reaction mixture was concentrated at 40° C. to remove phosphorylchloride and the residue was slowly quenched with water (40 mL) at <30°C. The resulting solution was basified with 50 wt % sodium hydroxidesolution and the resulting suspension was extracted with ethyl acetate(3×50 mL). The organic layers were concentrated to dryness and theresidue was purified by flash column chromatography using 40-50% ethylacetate/hexanes. The fractions containing the pure product wereconcentrated to dryness to afford a white solid, which was further driedunder vacuum at room temperature to afford the desired product as awhite solid (2.4 g, 49%): mp 104-106° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.93(d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7,1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 148.01, 142.72, 140.12, 135.99,128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]⁺).

Example 113-Chloro-N-(3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-yl)propanamide (5e)

A 100 mL, three-neck round bottom flask was charged with3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) andethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 6.17 mmol) was addedand the reaction mixture was cooled to 5° C. 3-Chloropropanoyl chloride(0.783 g, 6.17 mmol) was added dropwise at <20° C. The reaction wasallowed to warm up to 20° C. and stirred for 2 hours, at which pointthin layer chromatography analysis (Eluent: ethyl acetate) indicatedthat the reaction was complete. The reaction was diluted with water (50mL) and the layers separated. The aqueous layer was extracted with ethylacetate (20 mL) and the combined organic layers were concentrated todryness to afford a white solid (1.40 g, 96%): mp 152-154° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.07 (d, J=2.7 Hz, 1H), 8.89 (s,1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.23 (ddd, J=8.4, 2.7, 1.4 Hz, 1H),7.54 (dd, J=8.4, 4.7, Hz, 1H), 3.90 (t, J=6.2 Hz, 2H), 2.94 (t, J=6.2Hz, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 167.90, 147.50, 139.47, 135.46,133.47, 125.51, 124.20, 122.47, 119.87, 40.63, 37.91; ESIMS m/z 285([M+H]⁺).

Example 12N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(Compound 5.5)

A 100 mL, 3-neck round bottom flask was charged with3-chloro-N-(3-chloro-1-(pyridine-3-yl)-1H-pyrazol-4-yl)propanamide (570mg, 2.00 mmol) and methanol (10 mL), potassium hydroxide (135 mg, 2.40mmol) was added, followed by 3,3,3-trifluoropropane-1-thiol (312 mg,2.40 mmol) The mixture was heated at 50° C. for 4 hours, at which pointthin layer chromatography analysis [Eluent: ethyl acetate] indicated thereaction was complete to give exclusively a new product. It was cooledto 20° C. and diluted with water (20 mL) and ethyl acetate (20 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (20 mL). The organics were dried over sodium sulfate andconcentrated to dryness to afford a light yellow oil, which solidifiedupon standing to give a light yellow solid (700 mg, 92%): mp 99-102° C.;¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H), 9.05 (d, J=2.7 Hz, 1H), 8.86(s, 1H), 8.54 (dd, J=4.5, 1.4 Hz, 1H), 8.21 (ddd, J=8.4, 2.7, 1.4 Hz,1H), 7.54 (dd, J=8.4, 4.7 Hz, 1H), 2.86 (t, J=7.3 Hz, 2H), 2.74 (td,J=6.5, 5.6, 4.2 Hz, 4H), 2.59 (ddd, J=11.7, 9.7, 7.4 Hz, 2H); ¹³C NMR(101 MHz, DMSO-d₆) δ 169.32, 147.49, 139.44, 135.47, 133.40, 126.60 (q,J=296 Hz), 125.49, 124.23, 122.30, 120.00, 35.18, 33.42 (q, J=27.2 Hz),26.77, 23.05 (q, J=3.3 Hz); EIMS m/z 378 ([M]⁺).

Example 13 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride

A dry 5 L round bottom flask equipped with magnetic stirrer, nitrogeninlet, reflux condenser, and thermometer, was charged with3-((3,3,3-trifluoropropyl)thio)propanoic acid (188 g, 883 mmol) indichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) wasthen added dropwise over 50 minutes. The reaction mixture was heated toreflux (about 36° C.) for two hours, then cooled to room temperature.Concentration under vacuum on a rotary evaporator, followed bydistillation (40 Torr, product collected from 123-127° C.) gave thetitle compound as a clear colorless liquid (177.3 g, 86%): ¹H NMR (400MHz, CDCl₃) δ 3.20 (t, J=7.1 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 2.78-2.67(m, 2H), 2.48-2.31 (m, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.42, −66.43,−66.44, −66.44.

Example 14 3-(((2,2-Difluorocyclopropyl)methyl)thio)propanoic acid

Powdered potassium hydroxide (423 mg, 7.54 mmol) and2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) weresequentially added to a stirred solution of 3-mercaptopropanoic acid(400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. Theresulting white suspension was stirred at 65° C. for 3 hours andquenched with 1N aqueous hydrochloric acid and diluted with ethylacetate. The organic phase was separated and the aqueous phase extractedwith ethyl acetate (2×50 mL). The combined organic extracts were driedover magnesium sulfate, filtered and concentrated in vacuo to give thetitle molecule as a colorless oil (652 mg, 84%): IR (KBr thin film)3025, 2927, 2665, 2569, 1696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.85 (t,J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72 (m, 1H), 1.53 (dddd, J=12.3,11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1, 7.6, 3.7 Hz, 1H); ESIMS m/z195.1 ([M−H]⁻).

Example 15 3-(((2,2-Difluorocyclopropyl)methyl)thio)propanoyl chloride

In a 3 L 3-neck round bottomed-flask equipped with an overhead stirrer,a temperature probe, and addition funnel and an nitrogen inlet wascharged with 3-(((2,2-difluorocyclopropyl)-methyl)thio)propanoic acid(90.0 g, 459 mmol) that was immediately taken up in dichloromethane (140mL) with stirring. At room temperature, thionyl chloride (170 mL, 2293mmol) in dichloromethane (100 mL) was added drop-wise with stirring. Thereaction mixture was heated to 40° C. and heated for 2 hours. Thereaction was determined to be complete by ¹H NMR (An aliquot of thereaction mixture was taken, and concentrated down via rotaryevaporator). The reaction was allowed to cool to room temperature andthe mixture was transferred to a dry 3 L round-bottom flask andconcentrated via the rotary evaporator. This resulted in 95 g of ahoney-colored oil. The contents were gravity filtered through paper andthe paper rinsed with diethyl ether (10 mL). The rinse was added to theflask. This gave a clear yellow liquid. The liquid was placed on arotary evaporator to remove the ether. This gave 92.4 g of a yellow oil.The oil was Kugelrohr distilled (bp 100-110° C./0.8-0.9 mm Hg) toprovide the title compound as a colorless oil (81.4 g, 81%): ¹H NMR (400MHz, CDCl₃) δ 3.27-3.12 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.67 (ddd,J=6.8, 2.6, 1.0 Hz, 2H), 1.78 (ddq, J=13.0, 11.3, 7.4 Hz, 1H), 1.64-1.46(m, 1H), 1.09 (dtd, J=13.2, 7.7, 3.7 Hz, 1H).

Example 16 3-(3-Amino-1H-pyrazol-1-yl)pyridine (8a)

To a three-neck round bottomed flask (50 mL) equipped with a refluxcondenser was introduced 3-hydrazinopyridine.dihydrochloride (1.82 g,10.0 mmol) and anhydrous ethanol (10.0 mL). Sodium ethoxide (21 wt % inethanol, 11.8 mL, 31.5 mmol) was added over 5 minutes and the internaltemperature increased from 23° C. to 30° C. The resultant light brownslurry turned light pink after stirring for 10 minutes.3-Ethoxyacrylonitrile (2.06 mL, 20.0 mmol) was added over 5 minutes andthe internal temperature remained at 30° C. The yellow mixture wasstirred at 78° C. under nitrogen for 5 hours and was then cooled to 15°C. Hydrochloric acid (4 M in 1,4-dioxane, 2.90 mL) was added slowly toquench any excess base forming a light brown suspension. The mixture wasconcentrated under reduced pressure to afford a brown solid. The solidwas partitioned in water (30 mL) and ethyl acetate (50 mL). Theinsoluble light brown solid was collected by filtration to afford thefirst portion of product (0.340 g, >95% pure by ¹H NMR). The aqueouslayer was extracted with ethyl acetate (3×50 mL). The combined organicextracts were concentrated to afford dark brown wet solid. The mixturewas suspended in ethyl acetate (10 mL), filtered, and washed withheptane (20 mL) to afford the second portion of product as a brown solid(1.00 g, >95% pure by ¹H NMR). The title compound was obtained as abrown solid (1.34 g, 84%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=2.4Hz, 1H), 8.33 (dd, J=4.8, 1.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01(ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.42 (dd, J=8.4, 4.8 Hz, 1H), 5.80 (d,J=2.4 Hz, 1H), 5.19 (bs, 2H, —NH₂); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.7,144.7, 138.0, 136.2, 128.3, 123.9, 123.2, 97.1; EIMS m/z 160 ([M]⁺);HPLC (Zorbax SB-C8 column, P/N: 863954-306; mobile phase: A=water (0.1%formic acid), B=acetonitrile (0.01% formic acid); Gradient from 5 to100% acetonitrile over 15 minutes; flow: 1.0 mL/minute): t_(R)=1.95minutes.

Alternate Synthetic Route to: 3-(3-Amino-1H-pyrazol-1-yl)pyridine (8a)

A 4-neck round bottomed flask (500 mL) was charged with copper(I)chloride (2.51 g, 25.3 mmol), 1H-pyrazol-3-amine (15.8 g, 190 mmol),potassium carbonate (35.0 g, 253 mmol), and N,N-dimethylformamide (100mL). The mixture was stirred under nitrogen for 10 minutes and3-bromopyridine (12.2 mL, 127 mmol) was added. The mixture was heated at110° C. for 18 hours, at which point HPLC analysis indicated that ˜15.5%3-bromopyridine remained. The reaction was allowed to cool to 20° C. andconcentrated to give a brown residue. Water (200 mL) was added and theresulting suspension was stirred at 20° C. for 2 hours and filtered. Thesolid was rinsed with water (2×50 mL) and dried to afford a pale greensolid. The solid was suspended in water (200 mL) and the resultingsuspension was heated at 90° C. for 2 hours and was filtered hot througha Celite® pad. The pad was rinsed with hot water (50 mL). The combinedfiltrates were allowed to cool to 20° C. to afford a yellow suspension,which was stirred at 20° C. for 2 hours and filtered. The solid wasrinsed with water (2×50 mL) and air dried to afford the desired productas a light yellow crystalline solid (11.6 g, 57%).

Alternate Synthetic Route to: 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a)Step 1. 1-(Pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a)

To a 4-neck, round bottomed flask (250 mL) was charged sodium ethanolate(21 wt % in ethanol, 32 mL). 3-Hydrazinopyridine.dihydrochloride (5.00g, 27.5 mmol) was added, causing an exotherm from 20° C. to 58° C. Themixture was allowed to cool to 20° C. and acrylonitrile (2.91 g, 54.9mmol) was added. The reaction was heated at 60° C. for 5 hours andcooled to 20° C. The excess sodium ethanolate was quenched withhydrochloric acid (4 M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at <20° C.The mixture was absorbed on silica gel (10 g) and concentrated todryness. The crude product was purified by flash column chromatographyusing 0-10% methanol/dichloromethane as eluent. The fractions containingpure product were concentrated to dryness to afford the title compoundas a yellow solid (3.28 g, 74%): mp 156-160° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.24 (dd, J=2.8, 0.8 Hz, 1H), 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.22 (ddd,J=8.4, 2.8, 1.5 Hz, 1H), 7.12 (ddd, J=8.4, 4.6, 0.8 Hz, 1H), 4.20 (s,2H), 3.70 (t, J=9.3 Hz, 2H), 2.92 (t, J=9.3 Hz, 2H); ¹³C NMR (101 MHz,CDCl₃) δ 154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74;ESIMS m/z 163 ([M+H]⁺).

Step 2. 1-(Pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (8a)

To a 3-neck, round bottomed flask (100 mL) was charged1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (1.00 g, 6.17 mmol) andacetonitrile (20 mL). Manganese (IV) oxide (2.68 g, 30.8 mmol) wasadded, causing an exotherm from 20° C. to 25° C. The reaction wasstirred at 60° C. for 18 hours, after which it was filtered through aCelite® pad and the pad was rinsed with acetonitrile (20 mL). Water (20mL) was added to the combined filtrates and the resulting mixture wasconcentrated to 10 mL. Water (20 mL) was added and the resulting mixturewas again concentrated to 10 mL. The resulting suspension was stirred at20° C. for 18 hours and filtered. The filter cake was rinsed with water(2×5 mL) and dried to afford the title compound as a brown solid (0.680g, 69%).

Example 17 3-Chloro-1-(pyridine-3-yl)-1H-pyrazole-5-carboxylic acidhydrochloride (6e)

Methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (3.83 g, 16.1mmol) was stirred in dioxane (53.7 mL). The orange suspension was heateduntil a solution was achieved. Lithium hydroxide hydrate (1.01 g, 24.2mmol) in water (26.9 mL) was added to afford a darker red solution. Thereaction was stirred at room temperature for 1 hours, at which pointLCMS showed the corresponding acid to be the major product. The orangemixture was concentrated to dryness and the residue was mixed with 4 Nhydrochloric acid in dioxane (100 mL). The suspension was heated toreflux for 1 h and allowed to cool to room temperature. The resultingsuspension was filtered and the filter cake was rinsed with dioxane. Thesolid was vacuum dried at 50° C. to afford the desire product as a whitesolid (4.00 g, 91%): mp 244-246° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.00(dd, J=2.5, 0.7 Hz, 1H), 8.82 (dd, J=5.2, 1.4 Hz, 1H), 8.35 (ddd, J=8.3,2.4, 1.4 Hz, 1H), 7.85 (ddd, J=8.3, 5.2, 0.7 Hz, 1H), 7.25 (s, 1H); ¹³CNMR (101 MHz, DMSO-d₆) δ 158.71, 146.00, 143.44, 140.36, 137.00, 136.83,125.19, 111.71; ESIMS m/z 224 ([M+H]⁺).

Alternate Synthetic Route to:3-Chloro-1-(pyridine-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride

Methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (1.5 g, 6.0mmol) was stirred in concentrated hydrochloric acid (25 mL). Thereaction mixture was heated at reflux to afford a yellow solution. Afterheating overnight a solid had precipitated, and LCMS analysis of themixture indicated that the reaction was complete. The mixture wasallowed to cool to room temperature and dioxane (50 mL) was added. Themixture was concentrated to dryness. acetonitrile (50 mL) was added andthe resulting mixture was concentrated. The residue was vacuum dried at40° C. to afford the desired product as a yellow solid (1.6 g, 97%).

Example 18 Ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate

A 4-neck round bottomed flask (250 mL) was charged with sodium ethoxide(21 wt % in ethanol, 56 mL, 192 mmol).3-Hydrazinopyridine.dihydrochloride (10.0 g, 55.0 mmol) was added,causing an exotherm from 20° C. to 32° C. The reaction was allowed tocool to 20° C. and diethyl maleate (13.4 mL, 82.0 mmol) was added, andthe reaction was heated at 60° C. for 3 hours. The reaction was cooledto 20° C. and quenched with acetic acid. The reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were concentrated to dryness and the residue waspurified by flash column chromatography using ethyl acetate as eluent tothe title compound as a blue oil (6.60 g, 51%): ¹H NMR (400 MHz,DMSO-d₆) δ 10.40 (s, 1H), 8.40-8.26 (m, 1H), 8.19 (dd, J=4.4, 1.6 Hz,1H), 7.47-7.21 (m, 2H), 4.77 (dd, J=9.8, 2.1 Hz, 1H), 4.22 (qd, J=7.1,1.7 Hz, 2H), 3.05 (dd, J=17.0, 9.8 Hz, 1H), 1.99 (s, 1H), 1.25 (t, J=7.1Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.37, 146.60, 142.60, 137.28,123.54, 121.94, 65.49, 61.32, 32.15, 20.72, 13.94; ESIMS m/z 236([M+H]⁺).

Example 19 Ethyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate

A 3-neck round bottomed flask (100 mL) was charged with ethyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (8.50 g, 36.1 mmol) andacetonitrile (40 mL). Phosphoryl trichloride (4.05 mL, 43.4 mmol) wascharged and the reaction was heated at 60° C. for 2 hours. The reactionwas cooled to 20° C. and water (100 mL) was added. Sodium carbonate wasadded to adjust pH to 8 and the mixture was extracted with ethyl acetate(3×100 mL). The organic layers were concentrated to dryness and theresidue was purified by flash column chromatography using 30-80% ethylacetate/hexanes as eluent to provide the title compound as a yellow oil(7.30 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=2.9, 0.8 Hz, 1H),8.17 (dd, J=4.7, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.18(ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.79 (dd, J=12.4, 6.9 Hz, 1H), 4.24 (qd,J=7.1, 1.1 Hz, 2H), 3.55 (dd, J=17.7, 12.4 Hz, 1H), 3.33 (dd, J=17.8,6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 169.65,141.90, 141.33, 141.09, 135.13, 123.53, 120.37, 62.89, 62.35, 42.45,14.03; ESIMS m/z 254 ([M+H]⁺).

Example 20 Ethyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate

A 3-neck round bottomed flask (100 mL) was charged with ethyl3-chloro-1-(pyridin-3-yl)-1H-dihydropyrazole-5-carboxylate (2.00 g, 7.88mmol) and acetonitrile (20 mL). Manganese (IV) oxide (3.43 g, 39.4 mmol)was added, causing an exotherm from 20° C. to 21° C. The reaction wasstirred at 60° C. for 18 hours. Additional manganese (IV) oxide (3.43 g,39.4 mmol) was added and the reaction was stirred at 80° C. for 6 hours.The mixture was filtered through a Celite® pad and the pad was rinsedwith ethyl acetate (20 mL). The combined filtrates were concentrated todryness and the residue was purified by flash column chromatographyusing 10-60% ethyl acetate/hexanes. The pure fractions were concentratedto dryness to afford a white solid after drying (1.84 g, 93%): ¹H NMR(400 MHz, CDCl₃) δ 8.75-8.64 (m, 2H), 7.79 (ddd, J=8.2, 2.6, 1.5 Hz,1H), 7.42 (ddd, J=8.2, 4.8, 0.8 Hz, 1H), 6.98 (s, 1H), 4.27 (q, J=7.1Hz, 2H), 1.27 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 157.90,149.88, 147.01, 141.41, 136.24, 135.27, 133.34, 123.11, 111.97, 61.87,13.98; ESIMS m/z 252 ([M+H]⁺).

Alternate Synthetic Route to: Ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate

A vial (20 mL) was charged with ethyl3-chloro-1-(pyridin-3-yl)-1H-dihydropyrazole-5-carboxylate (0.500 g,1.97 mmol) and acetonitrile (5 mL). Sodium persulfate (0.799 g, 2.96mmol) was added, followed by sulfuric acid (0.733 g, 7.88 mmol) (Anexotherm was observed). The reaction was heated at 60° C. for 18 hours.The reaction was cooled to 20° C. and poured into water (20 mL). Themixture was basified with sodium carbonate to pH 9 and extracted withethyl acetate (2×20 mL). The organic layers were concentrated to aresidue, which was purified by flash column chromatography using 50%ethyl acetate/hexanes as eluent to provide the title compound as a whitesolid (0.280 g, 56%).

Example PE-1 Prophetic preparation of(2,2-difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 eq)in a solvent, such as methanol (at a concentration ranging from about0.01 M to about 1 M), at temperatures between about 0° C. and about 40°C. may be added thioacetic acid (about 1 equivalents to about 2equivalents), and a base, such as potassium carbonate (about 1equivalent to 2 equivalents). An additional amount of a base, such aspotassium carbonate (about 1 equivalent to 2 equivalents) may be addedafter a time ranging from about 30 minutes to 2 hours to the mixture toremove the acyl group. The reaction may be stirred until it isdetermined to be complete. The product may then be obtained usingstandard organic chemistry techniques for workup and purification.

Alternative Prophetic Preparation of:(2,2-Difluorocyclopropyl)methanethiol

To a solution of 2-(bromomethyl)-1,1-difluorocyclopropane (about 1 eq)in a solvent, such as methanol (at a concentration ranging from about0.01 M to about 1 M), at temperatures between about 0° C. and about 40°C. may be added thioacetic acid (about 1 equivalent to about 2equivalents), and a base, such as potassium carbonate (about 1equivalent to 2 equivalents). The intermediate thioester product maythen be obtained using standard organic chemistry techniques for workupand purification. To the thioester (about 1 equivalent) in a solvent,such as methanol (at a concentration ranging from about 0.01 M to about1 M), at temperatures between about 0° C. and about 40° C. may be addeda base, such as potassium carbonate (about 1 equivalent to 2equivalents). The reaction may be stirred until it is determined to becomplete. The product may then be obtained using standard organicchemistry techniques for workup and purification.

COMPARATIVE EXAMPLES Example CE-1 Oxidation of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) to3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) using iron (III) chloride

To a clear brown solution of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (0.480 g, 3.65 mmol) indry N,N-dimethylformamide (5.4 mL) in a round bottomed flask (25 mL) wasadded anhydrous iron (III) chloride (0.215 g, 1.33 mmol, 0.5 eq.)leading to a dark brown solution. Dried air was bubbled through themixture via a Teflon tube. The mixture was stirred at 100° C. for 19hours and cooled down to 40° C. LC-MS indicated disappearance ofstarting material along with significant amount (>50%) of side productsfrom α-dimerization (A): ESIMS m/z 325 ([M+H]⁺), and hydrolysis (B):ESIMS m/z 164 ([M+H]⁺) of starting material. The mixture wasconcentrated under vacuum and the residue was purified by flash columnchromatography using 0-60% ethyl acetate/hexanes as eluent to affordproduct that contains N,N-dimethylformamide. After drying under highvacuum for 16 hours, the title compound was obtained as a brown solid(0.164 g, 35%).

LC-MS Conditions: Phenomenex Kinetex C₁₈ column, 40° C., 1 μL injection;1 mL/min flow; 95% water (0.1% formic acid)/5% acetonitrile (0.05%formic acid), gradient to 50% acetonitrile (0.05% formic acid) over 15min., 3 min. post time. t_(r) (B)=2.18 min, t_(r) (A)=5.16 min, t_(r)(product)=6.27 min.

Example CE-2 Oxidation of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) to3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) using iron (III) chloride

To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (0.543g, 3.00 mmol) in dry N,N-dimethylformamide (6.0 mL) in a round bottomedflask (25 mL) was added anhydrous iron (III) chloride (0.146 g, 0.900mmol, 0.3 eq.) leading to a dark brown solution. The mixture was stirredat 85° C. when dried air was bubbled through the mixture via a Teflontube. LC-MS indicated 7.3% conversion into desired product along with20% conversion into dimeric side product (A) at 3.5 hours. After 22hours, LC-MS indicated 9.6% conversion into desired product along with22% conversion into dimeric side product (A). The reaction was stoppedand no further isolation was performed.

Example CE-3 Oxidation of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) to3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) using catalytic copper (I)chloride

To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (0.543g, 3.00 mmol) in dry N,N-dimethylformamide (3.0 mL) in a round bottomedflask (10 mL) was added copper (I) chloride (0.300 g, 0.300 mmol, 0.1eq.) leading to a green suspension. Dried air was bubbled through themixture. The resultant dark green mixture was stirred at 60° C. for 18hours and LC-MS indicated 1.8% conversion into desired product alongwith 0.7% conversion into dimeric side product (A). The mixture was notpurified.

Example CE-4 Oxidation of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) to3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) using catalytic copper (I)chloride

To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (0.543g, 3.00 mmol) in dry N,N-dimethylformamide (3.0 mL) in a round bottomedflask (10 mL) was added anhydrous copper (I) chloride (0.0590 g, 0.600mmol, 0.2 eq.) leading to a dark green suspension. The mixture wasstirred at 90° C. when dried air was bubbled through via a Teflon tube.The solution turned dark brown and LC-MS indicated 31% conversion intodesired product along with 8.3% conversion into dimeric side product (A)at 16 hours. After 22 hours, LC-MS indicated 35% conversion into desiredproduct along with 8.5% conversion into dimeric side product (A). Thereaction was stopped and no further isolation was performed.

Example CE-5 Oxidation of3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) to3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) using potassium persulfate inacetonitrile

To a solution of 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (0.181g, 1.00 mmol) in dry acetonitrile (3.0 mL) in a round bottom flask (10mL) was added potassium persulfate (0.405 g, 1.50 mmol, 1.5 eq.). Themixture was cooled in an ice-water bath. Sulfuric acid (conc., 0.106 mL,2.00 mmol, 2.0 eq.) was added slowly and the mixture was stirred at 80°C. for 6 hours. Sticky brown solid was formed at the bottom of the flaskand contained mostly starting material by LC-MS. LC-MS of the solutionindicated only starting material and no conversion into desired product.

Example CE-6 Alkylation Versus Retro-Michael-Like Decomposition

A suspension of sodium hydride (60% in oil, 1.03 eq) and solvent (1 vol)was stirred for 5 minutes.N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide(1 eq) dissolved in solvent (2 vol) was slowly added dropwise over 5minutes. Ethyl bromide (3.3 eq) and additive (0.22 eq) were addedsequentially. The suspension was then allowed to stir at roomtemperature until consumption of starting material was observed. Theselectivity of Compound 6.3 over the decomposition product wasdetermined by HPLC (See Table 2).

TABLE 2 Compound Time 8.5:Decomposition Entry Additive Solvent (hours)Product 1 tetrabutyl- N,N- 24  81:19 ammonium dimethylformamide iodide 2potassium N,N- 72 94:6 iodide dimethylformamide 3 potassiumN-methylpyrol- 20 92:8 iodide idinone

Example CE-7 3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine

Attempted Decarboxylation with Sulfuric Acid:

3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(1.00 g, 2.50 mmol) was dissolved in warm sulfolane (12.5 mL). sulfuricacid (1.35 mL, 25.0 mmol) was added and the reaction mixture was heatedto 100° C. After stirring for 1 hour, LCMS indicated that the reactiondid not occur. The reaction was further heated at 130° C. for 2 hours,at which point LCMS indicated no change. Additional sulfuric acid (4 mL)was added and the reaction was heated at 150° C. for 2 hours, at whichpoint LCMS showed a new major peak that did not correspond to desiredproduct.

Attempted Decarboxylation with Palladium (II)Trifluoroacetate/Trifluoroacetic Acid:

3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(1.00 g, 2.50 mmol) was dissolved in a mixture of dimethylsulfoxide(0.625 mL) and N,N-dimethylformamide (11.9 ml). Trifluoroacetic acid(1.93 ml, 25.0 mmol) was added followed by the addition of palladium(II)trifluoroacetate (0.332 g, 1.00 mmol). The reaction was heated at 100°C. overnight, at which time LCMS indicated that a reaction had occurredbut no desired product had been formed.

BIOLOGICAL EXAMPLES Example A Bioassays on Green Peach Aphid (“GPA”)(Myzus persicae) (MYZUPE.)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5-GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four posts with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testcompound. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test compound. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofthe cabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume acetone/methanol(1:1) solvent. Treated plants were held in a holding room for three daysat approximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.Corrected % Control=100*(X−Y)/X

-   -   where    -   X=No. of live aphids on solvent check plants and    -   Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitely adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Pesticidal activity was measured by using Abbott'scorrection formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) RatingTable Example Compound BEMITA MYZUPE 5a B B 5e A A Compound 5.5 B ACompound 8.5 A A Compound 9.5 A A % Control of Mortality Rating 80-100 AMore than 0-Less than 80 B Not Tested C No activity noticed in thisbioassay D

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

What is claimed is:
 1. A process comprising alkylating pesticidalthioether (3b)

with R²—X² in the presence of cesium carbonate and a polar solvent, toyield pesticidal thioether (3c),

wherein, X² is a leaving group, R¹ is selected from the group consistingof C₁-C₄-haloalkyl and C₁-C₄-alkyl-C₃-C₆-halocycloalkyl, and R² isselected from the group consisting of C₁-C₄-alkyl.
 2. The process ofclaim 1, wherein X² is halo, mesylate, or tosylate.
 3. The process ofclaim 1, wherein R² is methyl, ethyl or propargyl.
 4. The process ofclaim 1, wherein R²—X² is selected from the group consisting of methyliodide, ethyl bromide, ethyl iodide, propargyl chloride, propargylbromide, ethyl mesylate, propargyl mesylate, ethyl tosylate andpropargyl tosylate.
 5. The process of claim 1, wherein the polar solventis N,N-dimethylformamide.